Childhood onset, indolent progression, and risk of hepatic rupture: the natural history of hereditary lysozyme amyloidosis.

Background

Lysozyme amyloidosis (ALys) is a rare systemic amyloidosis caused by pathogenic variants in LYZ. We describe the natural history and outcomes for this disease in the largest cohort yet published.

Methods

All patients diagnosed with ALys at the National Amyloidosis Centre between 1988 and 2025 were included. Diagnosis was established by immunohistochemistry or proteomics with the identification of a variant in LYZ. Trends in data were analysed longitudinally.

Results

Thirty-five patients were included (median age: 45 years). Twenty-five (71%) carried the Asp67His (p.Asp85His) variant. Median age at symptom onset was 23.7 years, and 43% reported childhood symptoms. Sicca syndrome was the commonest presenting manifestation (46%), followed by gastrointestinal (GI) symptoms (23%). Renal involvement occurred in 57%. Eight developed kidney failure requiring renal replacement therapy. Six kidney transplants were performed with no amyloid recurrence. Liver involvement was present in 80%. Spontaneous hepatic rupture or haemorrhage occurred in five patients, necessitating emergency liver transplantation in four. GI bleeding occurred in 31%. Reproductive outcomes were successful in many patients.

Conclusions

ALys is characterised by early symptom onset, indolent systemic progression, and risk of catastrophic hepatic or splenic rupture. These findings provide a framework for surveillance, transplantation planning, and future therapeutic studies.